Type 1 diabetes is an autoimmune disorder characterized by the selective destruction of pancreatic beta-cells. Therapeutic strategies to prevent beta -cell loss and/or replenish beta -cell mass would be highly beneficial for the treatment of this disease. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone currently under investigation for use as a therapy for the treatment of type 2 diabetes. GLP-1 is an important regulator of the pancreatic beta-cell where it enhances glucose-induced insulin secretion, increases proinsulin biosynthesis and stimulates insulin gene expression. In addition to regulating a -cell function, GLP-1 is a mitogen for pancreatic E-cells. The mechanism of action of GLP-1 is likely to be exceedingly complex. In pancreatic a - cells, the GLP-1 receptor couples to Gs to stimulate adenylyl cyclase and increase cAMP production. Similar to GLP-1, cAMP potentiates glucose-stimulated insulin secretion and stimulates a -cell proliferation. Although many of the effects of cAMP are mediated through PKA, it is now evident that PKA-dependent and -independent signals mediate the effects of cAMP in beta -cells and other endocrine cells. In thyroid follicular cells where thyrotropin regulates thyroid hormone biosynthesis and secretion as well as cell renewal, PKA-dependent and -independent signals contribute to cAMP-regulated function and proliferation. The goal of the proposed studies is to assess the role of cAMP-mediated signaling in GLP-1 action. Further, the contribution of PKA-dependent and -independent signals to the regulation of beta -cell survival, proliferation and function are to be investigated. These studies will include an assessment of the roles of the small G protein RaplA, a direct target of cAMP, in a -cell growth and function, and of the transcription factor CREB, an important PKA target, in a-cell survival. The analysis of GLP-1 action will includes its effects on Akt and p70 ribosomal S6 kinase, protein kinases regulated selectively by cAMP in cells where it stimulates growth. The contribution of glucose and insulin/IGF-1 to GLP-1 effects in a-cells will be explored. Studies are to be carried out using rat insulinoma (INS-l) cells and all key findings confirmed in primary rat islets. The elucidation of the signaling modules through which GLP-1 regulates a-cell function, proliferation and survival will provide the fundamental knowledge required to facilitate the development of novel therapies for the treatment of diabetes.